Polymer derivative of 1-methyl-5/5-oxo-4-ethyl-tetrahydrofuryl-(3)-methyl/imidazole with cellulose glycolic acid

ABSTRACT

THE PRESENT INVENTION RELATES TO A NEW COMPOUND WHICH IS A POLYMER DERIVATIVE OF 1-METHYL-5-/5-OXO-4-ETHYLTETRAHYDROFURYL-(3)-METHYL/-IMIDAZOLE WITH CELLULOSE GLYCOLIC ACID OF THE GENERAL FORMULA   ((1-CH3,5-((4-(C2H5-),5-(O=)TETRAHYDROFUR-3-YL)-CH2-)-   2-IMIDAZOLINE . HOOC-CH2-O-)X-C6H7O2(-OH)(3-X))N   WHERE X IS SUBSTITUTION DEGREE FROM 75 TO 100, N IS POLYMERIZATION DEGREE FROM 30 TO 120. THE METHOD OF THE INVENTION FOR PRODUCING SAID POLYMER DERIVATIVE OF 1METHYL-5-/5-OXO-4-ETHYL-TETRAHYDROFURYL-(3)METHYL/-IMIDAZOLE WITH CELLULOSE GLYCOLIC ACID CONSISTS IN THAT 1-METHYL-5-/5-OXO-4-ETHYL-TETRAHYDROFURYL-(3)METHYL/-IMIDAZOLE IS REACTED WITH CELLULOSE GLYCOLIC ACID IN AN AQUEOUS MEDIUM, AND THE DESIRED PRODUCT IS SUBSEQUENTLY ISOLATED. SAID COMPOUND IS AN ACTIVE PRINCIPLE OF A MEDICINAL PREPARATION FEATURING M-CHOLINOMIMETIC ACTION.

United States Patent POLYMER DERIVATIVE 0F l-METHYL-S/S-OXO-4-ETHYL-TETRAHYDROFURYL (3) METHYL/ IMIDAZOLE WITH CELLULOSE GLYCOLICACID Nadezhda Alexandrovna Kashkina, ulitsaTalsu 99/11, kv. 22; MildaYanovna Pormale, ulitsa Suvorova 104, kv. 10; Arvid Yanovich Kalninch,ulitsa Sverdlova 8, kv. 3; Yanis Shusters, ulitsa Kveles 15, korpus 4,kv. 30; Guna Robertowna Dambite, ulitsa Gorkogo 37, kv. 20; IpatiyaMarcewna Reinberg, ulitsa Pumpura 5, kv. 8; Idea Wladimirowna Walkowa,ulitsa Mersroga 7, kv. 2; Wiya Aleksandrowna Tipaine, ulitsa Juglas 53,kv. 10; Autons Petrowich Skutelis and Stanislaws KazimirowichYankowskis, both of ulitsa Marupes 17, kv. 32; and Iuese Petrowna Olina,ulitsa Lachplesha 36, kv. 21, all of Riga, U.S.S.R.

No Drawing. Continuation of application Ser. No. 68,009., Aug. 28, 1970.This application June 23, 1972, Ser. No. 265,693

Int. Cl. C08b 11/14, 15/06 US. Cl. 260-213 3 Claims crn-cn-c n-onn wherex is substitution degree from 75 to 100, n is polymerization degree from30 to 120. The method of the invention for producing said polymerderivative of 1- methyl /5 oxo 4 ethyl tetrahydrofuryl-(3)-methyl/-imidazole with cellulose glycolic acid consists in i that1-methyl-5-/5-oxo 4 ethyl-tetrahydrofuryl-(3)- methyl/-imidazole isreacted with cellulose glycolic acid in an aqueous medium,'and thedesired product is subsequently isolated. Said compound is an activeprinciple of a medicinal preparation featuring M-cholinomimetic action.

This is a continuation of application Ser. No. 68,009, filed Aug. 28,1970, now abandoned.

The present invention relates to a new compound which is a polymerderivative of 1-methyl-5-/5-oxo 4 ethyltetrahydrofuryl (3)methy1/-imidazole with cellulose glycolic acid, and also to a method ofproducing the compound and application thereof.

Said new compound, according following general formula:

x is degree of substitution from 75 to 100, and n is degree ofpolymerization from 30 to 120.

3,812,099 Patented May 21, 1974 The compound proposed herein is anamorphous substance, slightly yellow in color, hygroscopic, readilysoluble in water, insoluble in organic solvents, decomposing under theaction of alkali.

Said compound features M-cholinomimetic action and is an activeprinciple of a medicinal preparation.

The medicinal preparation with M-cholinomimetic action, according to theinvention, comprises said active principle in combination with a diluentor an ointment base.

The mechanism of action of said medicinal preparation does not differfrom that of pilocarpine hydrochloride, but the present medicinalpreparation is noted for its greater activity and prolonged action. TheM-cholinomimetic activity of the present preparation was compared withthat of pilocarpine hydrochloride by testing 5-10 diiierentconcentrations (3-10-' mmol./lit.-5.i-10 mmol./lit.) of solutions ofsaid preparations on the M. rectus of the frog.

The exposure time for each of the test concentrations was 2 minutes,after which the muscle was washed to its initial tonus.

The experiments have shown the contraction to be always stronger (by asmuch as 1.5 times) with the present preparation, as compared topilocarpine, in case of applying the both preparations in the sameconcentrations to the same muscle.

Comparative tests of the M-cholinomimetic activity and duration ofaction of the proposed preparation and pilocarpine hydrochloride werecarried out on white rabbits. The animals were treated with solutions ofthe both preparations in concentrations from 0.0625 to 2 wt. percent, byinstillation. The myosis phenomena observed with white rabbits atvarious concentrations of the instilled preparations indicated theactivity and duration of action of the present preparation to be 1.5-3times greater than those of pilocarpine hydrochloride.

The present preparation was studied for acute toxicity on 102 whitemice, both male and female, by intraabdominal injection of 1-3%solutions of pilocarpine hydrochloride and of the present preparation indoses of -600 mg./kg. Each dose was administered to a group of animalscomprising 6-12 individuals.

The external clinical picture of the acuteintoxicat ion revealed noessential difierence between the present preparation and pilocarpine. f

The preparation proposed herein finds application, mainly, in ophthalmiatrics for treating primary glaucoma, but it can also be used fortreating adynamic ileus, trombosis of the central vein of retina, acuteobstruction of the retinal artery, atrophy of the optic nerve, etc.

Said preparation was clinically tested on 48 patients suffering fromprimary glaucoma, both, hospitalized and ambulatory. The patientstreated with the present preparation were those whohad alreadypassed'their' course'of treatment with pilocarpine, physostigmine,phosphacol, tosmilene, e tc.,--butwith no sufiicient effect- A l2%solution of the present preparation wasinstilled to the patients3-4-times a day. The administration of the preparation resulted in areduction of the intraocular tension and in stabilization thereof. Inone third of the cases the therapeutical effect was complete, in anotherthird it was partial. No side eifects were observed, even when thepresent preparation was applied over a long period of time (more than ayear).

Said preparation is used in the form of aqueous solutions and ointments.According to the invention, bidistilled water is used as a diluent. Thecontent of the active principle in the aqueous solutions of thepreparation is 1.1-2.3 wt. percent.

In ointments aqueous lanoline, Vaseline are employed as a base orcarboxymethyl cellulose as a polymeric base.

The content of the active principle in ointments is 1.1-4.6 wt. percent.

The preparation is contraindicated for cataract in combination withglaucoma.

The method of producing said compound, i.e., a polymer derivative ofl-methyl--/5-oxo-4-ethy1-tetrahydrofuryl-(3)-methyl/-imidazole withcellulose glycolic acid, according to the invention, consists inreacting l-methyl- 5/5-oxo-4-ethyl-tetrahydrofuryl-(3)-methyl/-imidazole with celluloseglycolic acid in an aqueous medium, followed by isolation of the desiredproduct.

For enhancing the quality of the final product, the starting materials,that is, l-methyl-S-/5-oxo-4-ethyl-tetrahydrofuryl (3) methyl/-imidazoleand cellulose glycolic acid, are taken in equimolecular amounts.

To accelerate the reactions, cellulose glycolic acid is used in the formof an aqueous solution, obtained by passing an aqueous solution ofsodium salt of cellulose glycolic acid through an H-form cation exchangeresin.

The proposed method is etfected as follows.

Cellulose glycolic acid as the starting material is used either dry, oras an aqueous solution. The use of cellulose glycolic acid in the formof an aqueous solution reduces the reaction time by as much as 5-6times. The cellulose glycolic acid is reacted with1-methyl-5-/5-oxo-4-ethyltetrahydrofuryl-(3)-methyl/-imidazole in anaqueous medium.

The reaction of combination of cellulose glycolic acid with 1 methyl 5/S-oxo-4-ethyl-tetrahydrofuryl-(3)- methyl/-imidazole ispolymer-analogous; the polymerization degree of the cellulose glycolicacid does not change. The process of interaction is carried out underintense stirring, at room temperature. The end of the reaction ischecked by measuring the pH of the reaction medium (which should bewithin 6.8-7.2).

On completion of the process, the desired product is isolated either byprecipitating it in acetone or ethanol, or by lyophilic drying of theresulting solution. The yield of the desired product is 95-98 wt.percent.

For a better understanding of the present invention, given hereinbeloware examples illustrating the way in which the present method ofproducing said compound can be realized.

EXAMPLE 1 g. of cellulose glycolic acid (substitution degree 75 andpolymerization degree 80) are mixed with 100 ml. of water, and 7.6 g. of1-methyl-5 /5-oxo-4-ethyl-tetrahydrofuryl (3) methyl/-imidazole areadded thereinto. The mixture is stirred during 4 hours at roomtemperature. The pH of the solution is 6.9. Then the obtained solutionis filtered and lyophilically dried. The yield of EXAMPLE 2 10 g. ofsodium salt of cellulose glycolic acid (substitution degree 80 andpolymerization degree 80) are dissolved in 200 ml. of water, and theresulting solution is '4 passed through an H-forrn cation exchange resin(the volume capacity being 4.5-5 mg.-equiv./g.). A solution of celluloseglycolic acid is thus obtained, containing 4.5 wt. percent of celluloseglycolic acid. T0 100 ml. of the obtained solution there are added 3.6g. of l-methyl-5-/5- oxo 4-ethyl-tetrahydrofuryl-(3)-methyl/-imidazole.The process is carried out under stirring, at room temperature, during0.5 hr. The pH of the solution is 7.0. The resulting solution islyophilically dried. The yield of the desired product is 7.9 g. (97 wt.percent of the theoretical amount).

Calcd. (percent): N, 5.92;l-methyl-S-/5-oxo-4-ethyltetrahydrofuryl-(3)-methyl/-imidazole, 44.4.Found (percent) N, 5.8; l-methyl-5-/5-oxo-4-ethyl-tetrahydrofuryl-(3)-methyl/-imidazole, 43.8.

What is claimed is: 1. A water-soluble polymer of the general formula GH O (OH) (OCH COOH-N CCH;-OHCH-fl H H H H1O =0 wherein x is the degreeof substitution of from to 100 and n is the degree of polymerization offrom 30 to prepared by reacting1-methyl-5l5-oxo-4-ethyl-tetrahydro-furyl-(3)-methyl/-imidazole withcellulose glycolic acid.

2. A method of producing a water-soluble polymer of the general formula(11H: OQH1O2(OH); X(OCH;C0OH'N--CCHCHOHC2H5),

H H H2C\ =0 wherein v x is the degree of substitution of from 75 to 100and n is the degree of polymerization of from 30 to 120, comprisingreacting 1-methyl-5/5-oxo-4-ethyl-tetrahydrofuryl-(3)-methyl/-imidaz0lewith an aqueous solution of cellulose glycolic acid, said celluloseglycolic acid having a degree of substitution of from 75 to 100 and adegree of polymerization of from 30 to 120, until the pH of the reactionmixture equals 6.8 to 7.2, followed by separating the desired product.

3. The method of claim 2 wherein1-methyl-5/5-oxov4-ethyl-tetrahydrofuryl-(3)-methyl/-imidazole andcellulose glycolic acid are taken in equirnolecular amounts.

References Cited UNITED STATES PATENTS 2,772,999 12/ 1956 Masci etal.260-231 3,214,341 10/1965 Feinstone 260231 3,277,079 10/1966 Press260232 DONALD E. CZAI A, Primary Examiner R. W. GRIFFIN, AssistantExaminer US. Cl. X.R. 4241 80 UNITED STATES PATENT OFFICE CERTIFICATE OFCORRECTION Patent No. 3812099 Dated May 21', 1.974

Inventor(s) Nadezhda A. Kashkina et a1 It is certified that errorappears in the above-identified patent and that said Letters Patent arehereby corrected as shown below:

[30] Foreign Priority Data USSR No. 1375103 filed November 11, 1969Signed and sealed this 4th day of February 1975.

(SEAL) Attest:

McCOY M. GIBSON JR. Attesting Officer C. MARSHALL DANN Commissioner ofPatents

